Disodium 2,2'-dithiobis ethane sulfonate (dimesna), and other salts and derivatives thereof, are known chemotherapeutic protective agents used to mitigate the toxicity of platinum complex antitumor drugs which are given to patients with certain types of cancer. Disclosure of dimesna and like compounds as platinum protecting agents are found in U.S. applications, Ser. No. 08/338,379, filed Nov. 14, 1994, Ser. No. 08/553,005, filed Nov. 3, 1995, and elsewhere in the literature.
Dimesna is a physiological auto-oxidation product of sodium 2-mercaptoethane sulfonate (mesna), which is also a protective agent for chemotherapeutic drugs. The structures of the preferred sodium salts (disodium in the case of the dianionic dimesna molecule) of mesna and dimesna are seen below as formula I and formula II, respectively. ##STR1##
Both mesna and dimesna have been used with varying degrees of success as protective agents for administration with platinum complex anti-tumor drugs. In particular, dimesna has been shown to be effective in providing protection against cisplatin (cis-diammine dichloro platinum) induced nephrotoxicity, and both mesna and dimesna have been shown to be effective against carboplatin (cis-diammine-1,1 cyclobutane dicarboxylato platinum) induced myelosuppression. Mesna has also been used as a protective agent with other antitumor drugs, and is approved for such use in the United States and a number of foreign jurisdictions. Full disclosures on the action of mesna, dimesna, and derivatives of each is found in one or more of the above referred documents, and more may also be found in the published literature. The wide-ranging utility of both mesna and dimesna as protective agents has been established in this art.
As mentioned above, mesna is auto-oxidized in the body to dimesna under mildly basic conditions and in the presence of oxygen, such as those present in plasma. Prior synthetic methods of making dimesna involved the oxidation of mesna to form its dimer (dimesna) in substantially quantitative yield. This synthesis was accomplished by reacting the dissolved mesna with an oxidizing agent which contained a source of elemental iodine as the oxidant, or in iodate form in an aqueous medium.
The prior art processes for synthesizing mesna and dimesna (and like sulfhydryls and disulfides) include the conversion of various alkyl sulfonic acids into their respective mercaptane derivatives and the subsequent oxidation into their respective disulfides by use of iodine-containing reagents as an oxidizing reagent. These processes, while efficient, required isolation procedures to be performed to isolate and purify the end products from the reagents used. Further, environmental pollutants were generated by the prior art processes which required disposal. Finally, the prior art processes could not be carried out in a single-pot process.